Background: Thyroid cancer is one of the fastest growing cancer diagnoses in the United States. Non-medullary thyroid cancer accounts for 95% of all thyroid cancer cases. Up to 8% of all non-medullary thyroid cancers are hereditary. Familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic disease. The best approach for screening at risk family members for FNMTC is unknown. The goal of this project is to determine the natural history and best screening strategy for FNMTC, and to identify susceptibility gene(s) for FNMTC. Summary: Because approximately 85% of disease causing mutations occur in the exome, we hypothesized that if there is a genetic basis for familial nonmedullary thyroid cancer (FNMTC) that these changes are likely to be present in the exome and have performed whole-exome sequencing of germline DNA in highly informative kindred with FNMTC. We have identified several candidate susceptibility genes in kindreds that we are currently validating, as well as, evaluating their function role in cancer initiation and progression. From our prospective screening clinical protocol in 25 kindred with a median follow up time of 4.3 years, we have detected thyroid cancer in 21.2% of patients with 3 or more first-degree relatives affected with FNMTC. Screening was associated with the detection of lower risk thyroid cancer and the youngest age of onset of thyroid cancer was 18 years of age. This is the first prospective study that clearly shows screening of at risk family member results in an earlier detection of low-risk FNMTC and leads to a less aggressive initial treatment. Moreover, our findings suggest that screening thyroid ultrasound should be started in teenage years in kindred with 3 or more family members affected by FNMTC.